Balloon dilatation of the coronary arteries is extremely effective in treating patients suffering from angina due to coronary artery disease, with an initial success rate of over 90%. However, restenosis occurs in 25-50% of patients, a process caused by injury-induced activation of smooth muscle cells (SMC) that reside in the arterial wall. After balloon injury the SMC proliferate excessively, thereby obstructing the artery and impeding blood flow. We are attempting to define the molecular basis of SMC proliferation so as to develop novel approaches to prevent restenosis based on the molecular response to injury. The first approach we are developing involves the use of transcriptional gene products that can specifically target, and thereby inhibit, synthesis of mitogenic proteins. This can be achieved by transfecting cells with a gene that encodes an inhibitory factor, or one that overexpresses a mutant form of the mitogen that, with the mutation, is devoid of mitogenic effect. The second approach is to use antisense strategies. Proteins are synthesized by translation of mRNA, which consists of a series of nucleotides encoding a message that designates a specific protein. This is called the "sense" message. The sequence of nucleotides that are its exact complement is called "antisense" -- it does not encode any message that can be translated into a protein. The antisense sequence binds to the sense mRNA, making it impossible for the mRNA to be translated into its protein. Antisense inhibition of translation can be accomplished either by using oligodeoxynucleotides (ODNs), or by transfecting cells with DNA that encodes antisense mRNA. For these approaches to succeed, the precise sequence of the target mRNA must be known. Because we have developed a rabbit model of vascular injury, we must know the rabbit DNA sequences to test our concepts in vivo. This year we have cloned and sequenced rabbit genes encoding EGF, IGF-I, FGF, and cyclin B1.